Radiotherapeutic Agents
Radiotherapy using "non-sealed sources" by way of radiolabeled pharmaceuticals has been employed for several decades [1-3]. Less than a handful of therapeutic pharmaceuticals are currently in routine use in the United States and approved by FDA. Recently, there has been renewed interest in developing new agents due to the emergence of more sophisticated molecular carriers, such as monoclonal antibodies, more capable of selective targeting of cancerous lesions. In addition, the identification of different radionuclides [4-7] with different chemical properties that have physical decay properties that are desirable for therapeutic application has further spurred development of new agents.
Although there has been some success in treatment of specific malignant diseases, many problems remain to be solved in this area. For example, in most cancers, it has been difficult to provide acceptable selectivity in radiation doses delivered to target tissues relative to normal tissues. Successful development of new therapeutic radiopharmaceuticals will require improved localization of these agents in target tissues and increasing rates of clearance from non-target tissues. In both of these situations, it is imperative that the therapeutic radionuclide remain firmly associated with the radioactive drug in vivo for extended periods of from a few hours up to several days. The length of time required will depend upon the pharmacokinetic and physical half-life of the radionuclide. No single radionuclide will be appropriate in formulating therapeutic agents since different half-lives and the energy of emitted particles will be required for different applications [4-7], making it essential that radiopharmaceuticals with different radionuclides be made available.
It is expected that therapeutic agents will be primarily labeled with beta-particle emitting radionuclides for the near future. Several different chelating structures have been employed to maintain the association of these beta emitters with the drug [8-12]. Many of the chelating structures are not sufficiently stable and most, if not all, do not provide appropriate routes or rates of clearance of radioactivity from non-target tissues [13,14]. This results in delivery of high radiation doses to normal tissues and reduces the therapeutic ratio which in turn lowers the amount of radiation dose that can be safely delivered to target tissues, such as tumors or micrometastases. Development of new radionuclide chelates that link the radioactive metal to the radiopharmaceutical is presently necessary. These complexes must be highly stable in vivo while attached to the biomolecules and have improved clearance characteristics from normal tissues after catabolism of the antibody.
Diethyltriaminepentaacetic acid (DTPA) forms a rather stable chelate with a variety of metals and is exemplary of prior art chelating moieties. However, coupling of this ligand to monoclonal antibodies by one of its five carboxyl groups resulted in unacceptable in vivo stability with a variety of radionuclides [15]. Linking of DTPA by a side group attached to one of the carbon atoms on an ethylene bridging group provides improved in vitro and in vivo stability [16]. However, the stability characteristics are not ideal and clearance activity from certain organs such as kidney and liver, are poor [17].
Chelating agents based on the diamidodithiol (DADT) and triamidomonothiol (TAMT) backbones are another example of chelating agents that are used for forming small and stable hydrophilic complexes with .sup.186 Re, .sup.188 Re and .sup.99m Tc [18,19]. Since the chelation chemistry of .sup.99m Tc and Re are often identical [20], compounds labeled with .sup.99m Tc, using the same bifunctional chelating agents used for .sup.186 Re/.sup.188 Re, should also make useful diagnostic imaging agents. There are presently labeled monoclonal fragment products for diagnostic and therapeutic applications being made [21]. These immunochelates provide improved clearance characteristics from the liver, however, kidney retention of activity when using Fab or F(ab).sub.2 fragments of monoclonal antibodies labeled with these radionuclide chelates is higher than desirable [22].
Another example is the macrocyclic tetraamine-based chelating agent that also has four methylene carboxylate side arms (teta or DOTA) that has been used to form a .sup.67 Cu complex that has high in vitro and in vivo stability when linked to monoclonal antibodies. This chelate was first described for monoclonal antibody bioconjugation by Meares and coworkers [23]. This is a large chelate that shows promise, however, clearance activity from non-target organs such as liver and kidney have not been shown to be more efficient than the DADT or TAMT type chelates.
Other non-antibody based radiodiagnostic or radiotherapeutic agents (e.g., chelates, small peptides, receptor agents) have also been considered for applications in humans [24-27]. New types of these agents would also be valuable where firm linking of the radionuclide to these compounds may also prove beneficial.